Mechanisms of regeneration in post stroke dementia

PhD ThesisStroke is a leading cause of morbidity, disability and cognitive impairment. Approximately, 25% of post stroke survivors develop dementia in the subsequent five years after initial cerebrovascular injury. However, the majority of individuals maintain their cognitive function. The cognitive function after stroke (CogFAST) study was established to assess the long term consequences of ischemic injury in the elderly, determine the types of dementia inherent in stroke survivors and to elucidate the pathological substrates of cognitive impairment. The aim of this specific study was to determine whether regenerative mechanisms, specifically angiogenesis and neurogenesis, could explain the variance in cognitive status of post stroke survivors; those who succumbed to dementia (PSD) compared to those who did not (PSND). We also compared subjects with Alzheimer’s disease (AD) and vascular dementia (VaD) and aged match controls. Quantitative histopathological methods were used to assess microvascular density and neurogenic markers in post-mortem human tissue. Vascular density was assessed using a morphometric technique based on stereology and found significant increases in both PSD and AD compared to all other groups. A significant increase in vessel diameter was also observed in PSND compared to other groups. Changes in expression of pro-angiogenic molecules hypoxic inducing factor 1α, integrin and vascular endothelial growth factor were assessed, with an increase reported in PSD and AD. Differences in expression of neurogenic markers in the dentate gyrus were noted, generally an increase was observed in a number of markers in VaD subjects compared to other groups. Significant decreases in expression in PSND and AD were also found compared to control groups. A reduction in expression was reported, in all dementia groups, for Hu C/D. Further analysis was performed using the neuronal marker Hu C/D in the hippocampus, which has been suggested to be involved in neuronal maintenance and plasticity. An increased in expression in the Cornu Ammonis 1 (CA1) in PSND subjects compared to all dementia groups. Significant reductions were also reported in VaD cases in a number of regions of the hippocampus compared to controls and PSND subjects. Although, significant differences were found between PSND and PSD cases, the data did not produce conclusive evidence that either angiogenesis or neurogenesis could explain the maintenance of cognitive function in PSND subjects. A number of similarities were also found between PSD and AD subjects, which may suggest an underlying similar mechanism.Alzheimer Research UK